Hepatocellular carcinoma (HCC) accounts for 85% of primary malignant tumors of the liver and is the third most-common cause of cancer-related death in the world. Although its etiology is diverse, the development of HCC follows a common pathogenic profile with repetitive hepatic injury leading to cirrhosis, formation of hyperplastic nodules and accumulation of genetic aberrations. Using a forward genetic approach, we have identified an N-ethyl-N-nitrosourea (ENU)-induced germline mutant phenotype, called Sphinx that develops spontaneous multicentric liver tumors. Tumor formation is apparent by 5 weeks of age and histological analyses revealed that the tissue is well differentiated and no etastases were observed. In addition to hepatocellular tumor development, homozygous Sphinx mice exhibit abnormal lymphocyte development and lack peripheral CD8+ T and NK cells. The phenotypes behave as recessive traits and C57BL/6JSphinx/Sphinx mice die by 12 weeks of age. Coarse mapping placed the mutation in a small interval on chromosome 6, in which no obvious candidate genes were found. The goal of this proposal is to identify the gene carrying the mutation responsible for the described phenotypes. In addition, we intend to characterize the Sphinx phenotype in more detail and to study the interaction between the immune system and tumor cell development. We believe our studies will reveal a novel gene involved in HCC development and provide a new, useful, model system in which to study the interaction between the immune system and hepatocellular tumor formation. PUBLIC HEALTH RELEVANCE: The studies are aimed to identify a yet unknown tumor suppressor gene involved in hepatocellular adenoma/carcinoma development. In addition, using a unique mouse model identified in our laboratory, we aim to study the involvement of the immune system in the pathophysiology of hepatocellular tumor development.